Non-Invasive Fractional Flow Reserve (FFR) for Stable Ischemic Heart Disease

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member

Title XVIII of the Social Security Act, §1862(a)(1)(D) items and services related to research and experimentation

Title XVIII of the Social Security Act, §1862(a)(7) states Medicare will not cover any services or procedures associated with routine physical checkups

42 CFR §410.32 indicates that diagnostic tests may only be ordered by the treating physician (or other treating practitioner acting within the scope of his or her license and Medicare requirements)

42 CFR §414.92 codifies the Appropriate use Criteria Program policies

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Part 4, §220 Radiology

The Protecting Access to Medicare Act (PAMA) of 2014, §218(b), established a new program to increase the rate of appropriate advanced diagnostic imaging services provided to Medicare beneficiaries

Coverage Guidance, Limitations, and Reasonable and Necessary Criteria

Noninvasive Fractional Flow Reserve (FFR_CT)

Noninvasive fractional flow reserve deduced from computed tomography (FFR_CT) involves computer-assisted processing of coronary computed tomography angiography (CCTA) images to estimate changes in blood pressure inside coronary arteries that have partial blockages, with the goal of determining how severely the blockages impede blood flow to the heart. FFR_CT is a post-processing software for the clinical quantitative and qualitative analysis of previously acquired computed tomography (CT) Digital Imaging and Communications in Medicine (DICOM) data for clinically stable symptomatic patients with coronary artery disease (CAD). FFR_CT analysis is intended to support the functional evaluation of CAD. The results of this analysis are provided to support qualified clinicians to aid in the evaluation and assessment of coronary arteries.

United States (U.S.) Food and Drug Administration (FDA) approved non-invasive calculated coronary fractional flow reserve (FFR_CT) technology derived from CCTA may be reasonable and necessary to guide qualified-provider decisions about the use of invasive coronary angiography (ICA) in clinically stable symptomatic patients with CAD of unknown functional significance, a technically adequate CCTA AND the following criteria:

Intermediate risk* patients with acute or stable chest pain and no known coronary artery disease, with coronary artery stenosis of 40-90% in proximal or middle coronary artery on CCTA

OR

Intermediate risk with acute chest pain and known non-obstructive (<50%) CAD with findings of coronary artery stenosis of 40-90% in a proximal or middle coronary artery on CCTA

OR

Stable nonobstructive coronary artery disease (<50% stenosis) with persistent symptoms requiring further test, and findings of 40-90% stenosis on CCTA

AND

Not in conjunction with stress testing (unless CCTA was not sufficient quality for FFR_CT and an alternative study is needed)

FFR_CT testing is not reasonable and therefore not covered for patients with the following conditions:

• Bare metal intracoronary stent
• Prosthetic valves
• Heart transplantation
• Recent prior myocardial infarction (MI) within 30 days
• Suspicion for acute coronary syndrome (where acute MI or unstable angina have not been ruled out)
• Patients with prior pacemaker or internal defibrillator lead implantation
• Post coronary artery bypass surgery
• Newly diagnosed systolic heart failure with no prior left heart catheterization
• Non-obstructive CAD (<50% stenosis in all major epicardial vessels) on prior CCTA or prior catheterization, performed in last 12 months in the absence of a new symptom complex
• *If turnaround times may impact prompt clinical care decisions

*Intermediate and high-risk is as defined in the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain²⁷

This service should be performed in patients with stable coronary symptoms. It should not be performed until after the base study (CCTA) has been completed and interpreted. If higher grade stenoses (i.e., greater than 90%) are present, this study is not medically necessary, as the patient should proceed to catheterization. Similarly, low-grade stenoses (less than 40%) do not require additional confirmatory data. This should be performed as an alternative to stress testing. 

Ischemic heart disease is a significant public health problem with an estimated prevalence of greater than 1 in 3 adults in the U.S. with some form of cardiovascular disease, including =40 million estimated to be = 60 years of age.³ Stable ischemic heart disease (SIHD) is diagnosed by symptoms (e.g., chest pain or ‘ischemic equivalents’ such as shortness of breath (dyspnea), neck/jaw or arm pain, palpitations, dizziness, syncope/near syncope) that are reproducible primarily with exertion and are not progressing in severity. The diagnostic approach for patients with symptoms that suggest SIHD, is to determine whether such symptoms represent the initial clinical recognition of chronic stable angina, a correlate of supply/demand mismatch precipitated by a change in activity or concurrent illness (e.g., anemia or infection).⁴ Invasive coronary angiography (ICA) is frequently unnecessary in patients with suspected SIHD, as evidenced by low diagnostic yields for significant obstructive CAD. For example, from a sample of over 132,000 ICAs, Patel, et al. found 48.8% of elective ICAs performed in patients with what was thought to be stable angina did not detect obstructive CAD (left main stenosis =50% or =70% in a major epicardial or branch >2.0 mm in diameter).⁵ Moreover, for the large majority of patients with SIHD, revascularization offers no survival advantage over medical therapy.¹ Noninvasive CCTA is very sensitive in detecting obstructive CAD, but is limited in its positive predictive value.⁶ CCTA also does not assess the functional significance of visualized lesions, and often leads to further evaluation with either stress testing or invasive angiography, or both.⁷

Determination of Functionally Significant CAD Using Vessel Anatomy and FFR_CT

Although it is recognized that individual coronary anatomy is highly variable, the anatomic construct for CAD is based on the presence or absence of flow-limiting obstructions in the coronary arteries categorized by the number of vessels involved (1-, 2-, and 3-vessel, and/or left main CAD) as well as the amount of myocardium at risk.¹

Although imperfect, the commonly used classification of 1-, 2-, and 3-vessel disease and left main disease remains widely used in clinical practice.¹ The coronary artery anatomy derived from CCTA can now be augmented with information derived from the physiologic testing of stenosis with FFR_CT technology.^8,9 The COURAGE investigators, along with outcome data from other trials involving more than 5,000 patients, confirmed that PCI (percutaneous coronary intervention) can be safely deferred with use of optimal medical therapy (OMT) in patients with stable CAD, even in those with multi-vessel involvement and inducible ischemia.^10-13 The accepted standards for coronary revascularization in patients with SIHD are outlined in collaborative, multi-society guidelines that define appropriate use criteria for coronary revascularization in patients with SIHD.^1,4 These management recommendations are determined by the number of vessels, vessel type, location of stenosis, and intensity of medical therapy.¹ When applied to the decision-making for revascularization, FFR_CT proves useful in providing information to characterize vessel disease when PCI is a consideration, as opposed to when optimal medical therapy is recommended.

Selective FFR_CT Guides Determination for Invasive Coronary Angiography

There is evidence, provided by 2 prospective and 2 retrospective cohort studies, that compares health outcomes observed during 90-day to 1-year follow-up for strategies using CCTA particularly in combination with selective FFR_CT with strategies using ICA or other noninvasive imaging tests.

The PLATFORM trial was a prospective, longitudinal, comparative-effectiveness study designed to assess the impact of using FFR_CT on stable patients with suspected CAD and referred for ICA.^14,15 The primary endpoint (rate of ICA showing non-obstructive disease within 90 days) included a control cohort of 187 consecutive patients referred for ICA (“usual care”) and 193 patients referred instead to CCTA and FFR_CT. Exclusion criteria included suspicion of acute coronary syndrome, prior coronary artery bypass graft (CABG), prior PCI, and contraindications for CCTA which included BMI > 35 kg/m² (supplemental data online). Using information obtained from the FFR_CT analysis, clinicians were able to cancel 61% of planned ICAs leading to an 83% reduction in the primary endpoint of ICAs showing no obstructive disease. One-year outcomes reported that FFR_CT was safe to use with 0 adverse events for those patients with canceled ICA. It is important to note that this study examined a strategy of using FFR_CT to guide management among patients eligible to undergo CCTA testing. 88% of CCTAs performed were of sufficient quality to assess FFR_CT consistent with the fact that FFR_CT may not be technically feasible in all patients.¹⁴

The PROMISE FFR_CT study further supports use of FFR_CT for guiding referral to ICA.¹⁶ This retrospective, observational, cohort study examined whether FFR_CT accurately predicts coronary revascularization and adverse events. Using FFR_CT to selectively refer patients to ICA improved catheterization lab efficiency by showing a reduction in patients referred to ICA by 28% and an increase in the rate of ICA leading to revascularization by 24%. A positive FFR_CT value was significantly better than CCTA at predicting whether a patient had an adverse event or underwent revascularization. In a ‘real world’ patient population and study design resulting in sites not receiving specific FFR_CT training and feedback (including standard administration of nitroglycerin and appropriate image reconstruction), the image quality requirements for FFR_CT were much more significant. One-third (33%) of the CCTAs sent to the FFR_CT core laboratory were inadequate for FFR_CT analysis. It is also notable that the BMI of participants of the initial PROMISE CCTA study, the population from which this FFR_CT population was derived, reported to the mean BMI to be 30.5 ± 6.1kg/m².⁷

The ADVANCE registry (Assessing Diagnostic Value of Non-invasive FFR_CT in Coronary Care) included 5,083 patients with symptoms suggestive of angina from 38 centers in Europe, North America, and Japan.¹⁷ FFR_CT provided information to physicians that resulted in a change in the management plans in two-thirds of patients (66.9%), compared to the management plan after CCTA. The prospective international multi-center study also demonstrated that for patients with CAD by CCTA and a negative FFR_CT (>0.80), medical management was safe. There were 0 adverse events at 90 days for the 1592 patients in this group. This contrasts with 19 adverse events (10 death, 4 MI, and 5 hospitalization and urgent revascularization) in patients with positive FFR_CT (=0.80) (MACE hazard ratio 19.75, p<0.001). The investigators concluded that FFR_CT can identify patients in need of invasive assessment. Among patients whose post-FFR_CT management plan was revascularization and who underwent ICA, 72.6% were re-vascularized. FFR_CT effectively differentiated patients who needed further invasive assessment from those who could be managed with medical therapy. A total of 190 subjects did not have their CCTA examinations submitted for FFR_CT analysis at the site discretion: 111 because the invasive treatment decision was made due to the severity of the stenosis; 61 owing to minimal CAD; 9 because of multiple coronary stents; 2 because of CCTA exams not acquired in a fashion acceptable for FFR_CT analysis.¹⁷ BMI characteristics were not reported, however, the U.S. population studied made up less than 23% of the international registry that included patients from Canada, Europe, and Japan and it is not clear from the data if the mean BMI across sites significantly varied (supplemental data).

2-Year FFR_CT Data Demonstrate Positive Health Outcomes

Norgaard, et al. (NXT Trial) reported 2-year outcomes from a single-center, observational study that included 3,674 consecutive patients with stable chest pain. Participants had a median age of 60 ± 9 years and a BMI of 26 ± 4 kg/m² and were followed for a median of 24 months (range of 8-41 months) after evaluated with CCTA and selective FFR_CT.¹⁸ The results demonstrate the ability of physicians to use the FFR_CT service to differentiate patients in need of PCI or CABG from those who could be managed with OMT alone. Patients with intermediate stenosis (30-70%) by CCTA who had a negative FFR_CT (>0.80) had 2-year outcomes equivalent to patients with no to minimal stenosis (0-30%) by CCTA. The composite endpoint (all-cause death, MI, hospitalization for unstable angina, and unplanned coronary revascularization) was 3.9% for the intermediate stenosis/ FFR_CT negative group versus 2.8% for no to minimal stenosis by CCTA group (p=0.58). Additionally, patients with a positive FFR_CT (=0.80) who underwent invasive assessment had fewer MIs than those with a positive FFR_CT who were managed medically (1.3% versus 8.0%, p<0.001). This study demonstrated the safety of using FFR_CT information to select the best treatment for patients.

Positive Health Outcomes Demonstrated in Medicare Population

Lastly, clinical evidence evaluating 254 Medicare-eligible subjects in a sub-analysis for the NXT study found that FFR_CT has a high diagnostic performance compared to invasively measured FFR, identifying patients with hemodynamically significant obstructions with high sensitivity (85%) and specificity (79%) in subjects = 65 years old with stenosis in the intermediate range (30-70%).¹⁹ Over 90% of patients in the analysis had the intermediate range stenosis. The data also established that myocardial ischemia is unlikely in patients with FFR_CT > 0.80 (negative predictive value (NPV) of 93%) again supporting the role of CCTA with FFR_CT as a reliable gatekeeper to ICA and revascularization. Other notable characteristics of the study population include mean BMI of 26 ± 3 kg/m², normal LVEF of 62% ± 7, and normal renal function. Patient with acute coronary syndrome, previous coronary intervention or bypass surgery, or BMI > 35 kg/m² were excluded. Additionally, 12% (44) CCTA subjects were excluded due to CCTA image artifacts. Stringent protocols for CCTA acquisition and analysis were also notable with laboratories following quality standards as defined in the Society of Cardiovascular Computed Tomography (SCCT) guidelines.² This included oral and/or intravenous beta-blockers to achieve to target a heart rate of < 60 beats/min and sublingual nitrates to ensure coronary vasodilation.

Additional literature recommended by the America College of Cardiology (ACC) provided better insight into current anatomic applications and accuracy of the determinations. The SYNTAX family of randomized controlled trials demonstrated that PCI or stenting is a viable option in patients with 3 vessel disease, and in the application of this technology to decision-making regarding CABG or PCI. Use of FFR_CT to determine a functional SYNTAX Score (in the SYNTAX III study) reclassified 30% of patients to a lower score.^20,21,22 ACC also provided additional literature supporting accuracy of CCTA in obese patients.^23,24

Societal Guidance

The use of invasive FFR is endorsed by multiple societies, including the Society of Cardiac Angiography and Interventions (SCAI) and American College of Cardiology (ACC)^28,29 and European Society of Cardiology.³⁰

The 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary²⁷ added recommendation that FFR can be useful for diagnosis of vessel-specific ischemia and to guide decision-making regarding the use of ICA for 3 categories of patients.²⁷

1. Intermediate risk and previously unknown coronary stenosis of 40-90% in proximal or middle coronary artery
2. Intermediate risk with acute chest pain and known coronary stenosis of 40-90% in proximal or middle coronary artery
3. Known nonobstructive coronary with stable chest pain and stenosis from 40-90% on CCTA

The level of evidence was graded B-NR which represents moderate quality evidence from one or more well-designed, non-randomized study and/or meta-analysis of such studies, and a Class of Recommendation (COR) 2a which is moderate strength of recommendation which means benefits are felt to outweigh risk. In the clinical pathways they recommend FFR_CT or stress test. They stated an advantage of FFR_CT is not needing to order an additional test but should not be ordered in cases where CCTA imaging may be suboptimal or there is extensive plaque present when stress test is preferred. Additionally, FFR_CT should not be performed when a delay in the results could impact patient care.

Level of evidence – Good (I-IIb, with risks of bias)

These and other studies were discussed by the assembled subject matter experts in a formal Contractor Advisory Committee (CAC) discussion convened by Noridian Healthcare Solutions on June 18, 2019. Based on a review of the literature there was a consensus that FFR_CT is a useful modality in the guidance of and assessment of stable coronary artery disease. At the time of the initial policy there was not sufficient evidence to allow for obesity (BMI >39) and evidence supported vessel specific restrictions within stenosis range of 40-70% range.

Since this LCD became active the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary was published with guidelines for use of FFR_CT with a moderate strength recommendation to expand the role of FFR_CT in specific clinical settings as an alternative to stress test.²⁷ The LCD has been updated to reflect these guidelines changes.

Based on these guidelines the intermediate stenosis range on CCTA has been expanded to 40-90% and vessel specific limits revised. The 2021 recommendations include the use of the technology for intermediate-risk patients with acute chest pain and no known coronary artery disease, with coronary artery stenosis of 40-90% in proximal or middle coronary artery on CCTA. This does not reverse the previously established position that the technology is limited to individuals with stable coronary symptoms and not for use in the high-risk patients or when myocardial infarction has not been excluded. It should not be performed until after the base study (CCTA) has been completed and interpreted and should not be relied upon when a delay in the results could impact patient care.

The 2021 Guideline recommendations provide the option of FFR_CT or stress test in the clinical settings which it has been determined to be an alternative to stress test. Therefore, FFR_CT should be performed as an alternative to stress testing. Based on this recommendation a new requirement has been added that the FFR_CT will not be covered in conjunction with stress testing. In circumstances where the FFR_CT was not high quality and a report could not be generated then a stress test may be covered as the alternative test. While the FFR_CT offers the benefit of another test not needing to be performed at a separate time, clinical judgement will be necessary to limit to clinical circumstances that a high-quality FFR_CT study will be expected. Additionally, severe obesity is removed as a limitation based on publication of new literature to support its use in patients with BMI >39 if the scanner used for CCTA can enable high quality images in setting of severe obesity.

Abbara S, Blanke P, Maroules CD, et al. SCCT guidelines for the performance and acquisition of coronary computed tomographic angiography: A report of the Society of Cardiovascular Computed Tomography Guidelines Committee Endorsed by the North American Society for Cardiovascular Imaging (NASCI). J Cardio Computed Tomog. 2016(10):435-449.

Noridian Healthcare Solutions- Carrier Advisory Committee - June 18, 2019.

U.S. Food and Drug Administration (FDA), Center for Devices and Radiologic Health (CDRH). Coronary Vascular Physiologic Simulation Software: Heartflow FFR_CT. De Novo Number: DEN130045. November 6, 2013. Accessed 5/24/2022.

Washington State Health Care Authority, Health Technology Clinical Committee. Coronary Computed Tomographic Angiography. Final Findings and Coverage Decision. Olympia, WA: Washington State Health Care Authority; May 8, 2009.

Additional literature was reviewed^31-41

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26. Budde R, Nous F, Roest S, et al. Non-invasive functional coronary artery evaluation by CT-derived fractional flow reserve (FFRct) in heart transplant patients. Journal of Heart and Lung Transplantation. 2020;39(4):S62.
27. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: Executive summary: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2021;78(22):2218-2261.
28. Patel MR, Calhoon JH, Dehmer GJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease: A report of the American College of Cardiology appropriate use criteria task force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society of Thoracic Surgeons. J Nucl Cardiol. 2017;24(5):1759-1792.
29. Lotfi A, Davies JE, Fearon WF, Grines CL, Kern MJ, Klein LW. Focused update of expert consensus statement: Use of invasive assessments of coronary physiology and structure: A position statement of the society of cardiac angiography and interventions. Catheter Cardiovasc Interv. 2018;92(2):336-347.
30. Knuuti J, Wijns W, Saraste A, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020;41(3):407-477.
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32. Sud M, Han L, Koh M, et al. Association between adherence to fractional flow reserve treatment thresholds and major adverse cardiac events in patients with coronary artery disease. JAMA. 2020;324(23):2406-2414.
33. McNabney CG, Sellers SL, Wilson RJ, et al. Prognosis of CT-derived fractional flow reserve in the prediction of clinical outcomes. Radiology: Cardiothoracic Imaging. 2019;1(2):e190021.
34. Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: The task force on the management of stable coronary artery disease of the European Society of Cardiology. European Heart Journal. 2013;34(38):2949-3003.
35. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165.
36. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362(10):886-895.
37. Völz S, Dworeck C, Redfors B, et al. Survival of patients with angina pectoris undergoing percutaneous coronary intervention with intracoronary pressure wire guidance. J Am Coll Cardiol. 2020;75(22):2785-2799.
38. Hlatky MA, De Bruyne B, Pontone G, et al. Quality-of-life and economic outcomes of assessing fractional flow reserve with computed tomography angiography: PLATFORM. J Am Coll Cardiol. 2015;66(21):2315-2323.
39. Parikh RV, Liu G, Plomondon ME, et al. Utilization and outcomes of measuring fractional flow reserve in patients with stable ischemic heart disease. J Am Coll Cardiol. 2020;75(4):409-419.
40. Sonck J, Miyazaki Y, Collet C, et al. Feasibility of planning coronary artery bypass grafting based only on coronary computed tomography angiography and CT-derived fractional flow reserve: A pilot survey of the surgeons involved in the randomized SYNTAX III Revolution trial. Interact Cardiovasc Thorac Surg. 2019;29(2):209-216.
41. Budde R, Nous F, Roest S, et al. Non-invasive functional coronary artery evaluation by CT-derived fractional flow reserve (FFRct) in heart transplant patients. J Heart Lung Transplant. 2020;39(4):S62.

• FFR